An N-protected-β-aminoalcohol, e.g., such as (2R,3S)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4-phenylbutane, (2S,3R)-3-tert-butoxycarbonylamino-1-halo-2-hydroxy-4-phenylbutane, or the like and the corresponding N-protected-β-amino poxide are both useful as synthetic interm diates for medicine compounds, such as, e.g., HIV protease inhibitor, or the like.
Such an N-protected-β-aminoalcohol, e.g., (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane can be produced, e.g., by reducing (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone.
Likewise, (2S,3R)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane can be produced, e.g., by reducing (3R)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone.
Reduction of (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone with the use of an appropriate reductant produces, as a by-product, a diastereomer of the target compound, (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane.
More specifically, it is reported that when it is reduced with tri-tert-butoxy lithium aluminum hydride in ether, (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane as the undesired diastereomer is formed in an amount of about 1 equivalent per 5 to 8 equivalents of the (2R,3S) diastereomer as the target compound. (Refer to, e.g., the following reports with respect to stereoselective reduction of halomethylketone derivatives: P. Raddats et al; J. Med. Chem., 1991, 34, 11, 3269; A. A. Malik: The 3rd International Conference on Organic Process Research & Development, Development of a Commercial Process for 2S,3S and 2R,3S-epoxides, 10–12th Jul. 2000, Montreal; T. Archibald: Scientific Update Conference Manual, Chiral USA '99, Full Scale Chiral Separations Using SMB, 4th May 1999, San Francisco, Scientific Update; etc.). As might be understood from the above reports, production of (2R,3S)- or (2S,3R)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane involves serious problems of the impurity diastereomer having to be removed.
In the above reports is disclosed a method of isolating (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane by silica gel chromatography or high-speed liquid chromatography. These methods, however, may not be industrially preferable, because they need an expensive carrier and a large quantity of solvent, and are complicated ones and time-consuming.
The last report cited above discloses at page 3, that (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane can only be purified by crystallization upto 94:6 in terms of a ratio of the target compound to its undesired diastereomer (as the impurity), because it has a lower melting point and higher solubility than the undesired diastereomer, and that its purification to a higher level cannot be realized by recrystallization.
Japanese Patent Applicaton Laid-open (Kokai) No. 8-225557 (U.S. Pat. No. 5,481,011) discloses purification and isolation of a halohydrin by crystallization from an appropriate solvent, e.g., ethanol, methanol, isopropanol, toluene, aceton, acetonitrile, water or a mixture thereof. However, the patent document only describes, in the example section, crystallization/isolation of (2S,3S)-N-carbamate-protected-β-aminoalcohol, but is silent as to the effects on the purification and yield, of crystallization of (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane or the like, which is considered to be difficult to purify.
WO00/43357 discloses purification/isolation of (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane in the presence of a hydrocarbon-based solvent. However, a highly polar impurity is difficult to remove according to this method.